The present invention relates to inhibitors of the nuclear transcription factor kappaB (NF-xcexaB) and to their use in therapy. Specifically, the present invention relates to the use of 2-hydroxy-4-trifluoromethylbenzoic acid derivatives to inhibit the activation of the transcription factor NF-xcexaB.
The control of the expression of proteins plays a key role both in the maintenance of the normal function of cells and hence of organisms, as well as in the development of pathological processes. This control is effected through the so-called transcription factors. One of these factors is the group of proteins known as nuclear transcription factor NF-xcexaB, formed by a family of intimately related dimeric complexes. NF-xcexaB exists in an inactive form in the cytoplasm of many types of cells. In response to a stimulus, it becomes activated and is then translocated to the nucleus, where it binds to DNA and regulates the transcription of various genes. The activation of NF-xcexaB can be induced by several agents such as inflammatory cytokines (for example, tumor necrosis factor-alfa (TNF-xcex1) and interleukin-1beta (IL-1xcex2)), mitogens, bacterial lipopolysaccharides (LPS), viruses, oxidants (for example, H2O2 and ozone), phorbol esters and ultraviolet light. Among the various genes whose expression is regulated by NF-xcexaB, many genes involved in immune and inflammatory responses are included. Thus, among others, NF-xcexaB regulates the expression of proinflammatory cytokines such as IL-1xcex2, interleukin-2 (IL-2), interleukin-6 (IL-6), TNF-xcex1 and granulocyte-macrophage colony stimulating factor (GM-CSF); chemokines such as interleukin-8 (IL-8), RANTES, macrophage inflammatory protein-1xcex1 (MlP-1xcex1), monocyte chemotactic protein-1 (MCP-1) and eotaxin; inflammatory enzymes such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LO) and cytosolic phospholipase A2 (cPLA2); adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin; and receptors such as the interleukin-2 receptor and the T-cell receptor (P. J. Barnes and I. M. Adcock, Trends Pharmacol. Sci. 1997, 18, 46-50).
Dysfunctions in the activation of NF-xcexaB and its dependent genes have been associated with several pathologies such as acute inflammation, septic shock, transplant rejection, radiation damage, ischemia and reperfusion damage and neurodegenerative diseases (P. A. Baeuerle and T. Henkel, Annu. Rev. Immunol. 1994, 12, 141-179), asthma and other chronic inflammatory diseases (P. J. Barnes and I. M. Adcock, Trends Pharmacol. Sci. 1997, 18, 46-50), osteoporosis (Y. Abu-Amer and M. Mehrad Tondravi, Nature Med. 1997, 3(11), 1189-1190), and cancer (M. A. Sovak et al., J. Clin. Invest. 1997, 100 (12), 2952-2960). Moreover, elevated levels of NF-xcexaB have been detected in synovial tissue of patients with rheumatoid arthritis (H. Asahara et al., Biochem. Mol Biol. Int., 1995, 37(5), 827-32), in central nervous system samples of multiple sclerosis patients (D. Gveric et al., J. Neuropathol. Exp. Neurol. 1998, 57(2), 168-78) and in samples of atherosclerotic tissue (K. Brand et al., J. Clin. Invest. 1996, 97(7), 1715-22), and it has been described that amyloid xcex2 peptide, which accumulates in plaques of Alzheimer patients, activates NF-xcexaB in central nervous system cells (C. Behl et al., Cell 1994, 77, 817-827). A high increase in the nuclear translocation of NF-xcexaB has also been observed in dopaminergic neurons of patients with Parkinson""s disease (S. Hunot et al., Proc. Natl. Acad. Sci. USA 1997, 94(14), 7531-7536). Furthermore, NF-xcexaB has also been reported to be involved in the transcriptional activation of viruses such as human immunodeficiency virus (HIV), cytomegaloviruses, adenoviruses and herpesviruses.
On the other hand, it has been shown that the cytokines, inflammatory enzymes, adhesion molecules and other proteins whose expression is regulated by NF-xcexaB play an important role in a broad range of disorders such as inflammation; asthma; adult respiratory distress syndrome (ARDS); immunoinflammatory and autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, lupus and glomerulonephritis; arthrosis; septic shock; atherosclerosis; cancer; osteoporosis; preterm labour; transplant rejection; neurodegenerative diseases such as dementia, including Alzheimer""s disease, Parkinson""s disease and amyotrophic lateral sclerosis; and viral infections.
In view of the above, the agents which are able to modulate the activity of the transcription factor NF-xcexaB and/or the expression of genes which are dependent on this transcription factor could be of great utility as therapeutic agents for the treatment or prevention of the above-mentioned disorders. It is thus of great interest to find agents which are capable of regulating NF-xcexaB activity.
2-Acetyloxy-4-trifluoromethylbenzoic acid, better known by its International Nonproprietary Name (INN) triflusal, is a platelet aggregation inhibitor marketed for the treatment of thromboembolic diseases under the trademark Disgren(copyright). Its main metabolite, 2-hydroxy-4-trifluoromethylbenzoic acid (also known by the acronym HTB), also possesses a remarkable activity as platelet antiaggregant. Both compounds are described in U.S. Pat. No. 4,096,252.
The present inventors have found that, surprisingly, both triflusal and its metabolite, HTB, inhibit NF-xcexaB activation. Moreover, it has been found that both compounds are potent inhibitors of the expression of genes that are transcriptionally regulated by NF-xcexaB. Due to this new activity now discovered, triflusal and HTB are potentially useful in the treatment or prevention of disorders where the activation of NF-xcexaB and its dependent genes is involved, such as those mentioned above.
The present invention is based upon the finding that triflusal and its metabolite, HTB, are potent inhibitors of the activation of the transcription factor NF-xcexaB. As mentioned above, NF-xcexaB is an ubiquitous transcription factor that acts by binding to DNA, activating in this manner the expression of various genes, many of them involved in the immune and inflammatory response. The present invention shows that triflusal and HTB inhibit the activation of NF-xcexaB induced by various agents such as TNF-xcex1, immune complexes and LPS in several types of cells, such as human umbilical vein endothelial cells (HUVEC), macrophages and monocytes. Moreover, it is also shown that triflusal and HTB inhibit the expression of several proteins in whose transcriptional regulation NF-xcexaB is involved, such as for example VCAM-1, iNOS, COX-2, MCP-1 and TNF-xcex1. Therefore, triflusal and HTB are useful as therapeutic or preventive agents in those pathological situations where NF-xcexaB and/or the proteins whose expression is regulated by this transcription factor are involved.
Triflusal and HTB can be generically represented by means of formula I: 
wherein R represents hydrogen (HTB) or COCH3 (triflusal).
It is an object of the present invention to provide the use of a compound of formula I for the manufacture of a medicament useful for inhibiting the activation of the transcription factor NF-xcexaB. The use of a pharmaceutically acceptable salt of a compound of formula I or of a prodrug thereof are also encompassed within the scope of the present invention.
Another object of the present invention is to provide the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament useful for inhibiting the expression of genes which are dependent on and/or regulated by, at least partially, the transcription factor NF-xcexaB. In a preferred embodiment, the gene encodes IL-1xcex2, IL-2, IL-6, TNF-xcex1, GM-CSF, IL-8, RANTES, MIP-1xcex1, MCP-1, eotaxin, iNOS, COX-2, 5-LO, cPLA2, ICAM-1, VCAM-1, E-selectin, IL-2 receptor or T-cell receptor, and more preferably encodes VCAM-1, iNOS, COX-2, MCP-1 or TNF-xcex1.
It is also an object of the present invention to provide the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of disorders associated with the activation of the transcription factor NF-xcexaB and/or the expression of genes which are dependent on this transcription factor. In a preferred embodiment, the disorder is inflammation; asthma; adult respiratory distress syndrome (ARDS); immunoinflammatory and autoimmune diseases such as rheumatoid arthritis and other arthritic conditions, multiple sclerosis, psoriasis, inflammatory bowel disease, lupus and glomerulonephritis; arthrosis; septic shock; atherosclerosis; cancer; osteoporosis; preterm labour; transplant rejection; neurodegenerative diseases such as dementia, including Alzheimer""s disease, Parkinson""s disease and amyotrophic lateral sclerosis; and viral infections.
It is also an object of the present invention to provide the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament useful for inhibiting the expression of COX-2.
Another object of the present invention is to provide the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of diseases mediated by COX-2. In a preferred embodiment, the disease mediated by COX-2 is rheumatoid arthritis and other arthritic conditions, arthrosis, preterm labour, dementia or cancer.
It is also an object of the present invention to provide the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament useful for inhibiting the expression of VCAM-1.
It is also an object of the present invention to provide the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of diseases mediated by VCAM-1. In a preferred embodiment, the disease mediated by VCAM-1 is atherosclerosis, rheumatoid arthritis, lupus, multiple sclerosis, inflammatory bowel disease, asthma, allergic rhinitis and tumor metastasis.
Another object of the present invention is to provide the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament useful for inhibiting the expression of iNOS.
It is also an object of the present invention to provide the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of diseases mediated by iNOS. In a preferred embodiment, the disease mediated by iNOS is inflammation, septic shock, inflammatory bowel disease and neurodegenerative diseases.
It is also an object of the present invention to provide the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament useful for inhibiting the expression of TNF-xcex1.
Another object of the present invention is to provide the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of diseases mediated by TNF-xcex1. In a preferred embodiment, the disease mediated by TNF-xcex1 is rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis and other arthritic conditions, arthrosis, sepsis, septic shock, endotoxic shock, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, pulmonary fibrosis, hepatitis, osteoporosis and other bone resorption diseases, reperfusion injury, transplant rejection, multiple sclerosis, lupus, fever and myalgias due to infections, cachexia, acquired immune deficiency syndrome (AIDS), inflammatory bowel disease and pyresis.
It is also an object of the present invention to provide the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament useful for inhibiting the expression of MCP-1.
It is also an object of the present invention to provide the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of diseases mediated by MCP-1. In a preferred embodiment, the disease mediated by MCP-1 is atherosclerosis, glomerulonephritis, rheumatoid arthritis, pulmonary fibrosis, restenosis, asthma, psoriasis, inflammatory bowel disease, multiple sclerosis and transplant rejection.
It is also an object of the present invention to provide the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of neurodegenerative diseases, particularly dementia, Parkinson""s disease and amyotrophic lateral sclerosis.
It is also an object of the present invention to provide the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of immunoinflammatory and autoimmune diseases, preferably rheumatoid arthritis and other arthritic conditions, multiple sclerosis, psoriasis, inflammatory bowel disease, lupus and glomerulonephritis.
It is also an object of the present invention to provide the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of arthrosis.
It is also an object of the present invention to provide the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of cancer.
It is also an object of the present invention to provide the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of atherosclerosis.
It is also an object of the present invention to provide the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the prevention of preterm labour.
It is also an object of the present invention to provide the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of inflammation.
It is also an object of the present invention to provide the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of asthma or adult respiratory distress syndrome.
It is also an object of the present invention to provide the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of septic shock.
It is also an object of the present invention to provide the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of osteoporosis.
It is also an object of the present invention to provide the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of viral infections.
It is also an object of the present invention to provide the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament for the treatment or prevention of transplant rejection.
The present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for inhibiting the activation of the transcription factor NF-xcexaB.
The present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for inhibiting the expression of genes which are dependent on and/or regulated by, at least partially, the transcription factor NF-xcexaB.
The present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the treatment or prevention of disorders associated with the activation of the transcription factor NF-xcexaB and/or the expression of genes which are dependent on this transcription factor.
The present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for inhibiting the expression of COX-2.
The present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the treatment or prevention of diseases mediated by COX-2, preferably rheumatoid arthritis and other arthritic conditions, arthrosis, preterm labour, dementia or cancer.
The present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for inhibiting the expression of VCAM-1.
The present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the treatment or prevention of diseases mediated by VCAM-1, preferably atherosclerosis, rheumatoid arthritis, lupus, multiple sclerosis, inflammatory bowel disease, asthma, allergic rhinitis and tumor metastasis.
The present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for inhibiting the expression of iNOS.
The present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the treatment or prevention of diseases mediated by iNOS, preferably inflammation, septic shock, inflammatory bowel disease and neurodegenerative diseases.
The present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for inhibiting the expression of TNF-xcex1.
The present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the treatment or prevention of diseases mediated by TNF-xcex1, preferably rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis and other arthritic conditions, arthrosis, sepsis, septic shock, endotoxic shock, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, pulmonary fibrosis, hepatitis, osteoporosis and other bone resorption diseases, reperfusion injury, transplant rejection, multiple sclerosis, lupus, fever and myalgias due to infections, cachexia, acquired immune deficiency syndrome (AIDS), inflammatory bowel disease and pyresis.
The present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for inhibiting the expression of MCP-1.
The present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the treatment or prevention of diseases mediated by MCP-1, preferably atherosclerosis, glomerulonephritis, rheumatoid arthritis, pulmonary fibrosis, restenosis, asthma, psoriasis, inflammatory bowel disease, multiple sclerosis and transplant rejection.
The present invention also provides a method for inhibiting the activation of the transcription factor NF-xcexaB in a mammal in need thereof, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof. The mammal is preferably a human being.
The present invention also provides a method for inhibiting the expression of genes which are dependent on and/or regulated by, at least partially, the transcription factor NF-xcexaB in a mammal in need thereof, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof.
The present invention also provides a method for the treatment or prevention of disorders associated with the activation of the transcription factor NF-xcexaB and/or the expression of genes which are dependent on this transcription factor in a mammal in need thereof, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof.
The present invention also provides a method for inhibiting the expression of COX-2 in a mammal in need thereof, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof.
The present invention also provides a method for the treatment or prevention of diseases mediated by COX-2, preferably rheumatoid arthritis and other arthritic conditions, arthrosis, preterm labour, dementia or cancer, in a mammal in need thereof, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof.
The present invention also provides a method for inhibiting the expression of VCAM-1 in a mammal in need thereof, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof.
The present invention also provides a method for the treatment or prevention of diseases mediated by VCAM-1, preferably atherosclerosis, rheumatoid arthritis, lupus, multiple sclerosis, inflammatory bowel disease, asthma, allergic rhinitis and tumor metastasis, in a mammal in need thereof, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof.
The present invention also provides a method for inhibiting the expression of iNOS in a mammal in need thereof, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof.
The present invention also provides a method for the treatment or prevention of diseases mediated by iNOS, preferably inflammation, septic shock, inflammatory bowel disease and neurodegenerative diseases, in a mammal in need thereof, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof.
The present invention also provides a method for inhibiting the expression of TNF-xcex1 in a mammal in need thereof, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof.
The present invention also provides a method for the treatment or prevention of diseases mediated by TNF-xcex1, preferably rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis and other arthritic conditions, arthrosis, sepsis, septic shock, endotoxic shock, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, pulmonary fibrosis, hepatitis, osteoporosis and other bone resorption diseases, reperfusion injury, transplant rejection, multiple sclerosis, lupus, fever and myalgias due to infections, cachexia, acquired immune deficiency syndrome (AIDS), inflammatory bowel disease and pyresis, in a mammal in need thereof, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof.
The present invention also provides a method for inhibiting the expression of MCP-1 in a mammal in need thereof, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof.
The present invention also provides a method for the treatment or prevention of diseases mediated by MCP-1, preferably atherosclerosis, glomerulonephritis, rheumatoid arthritis, pulmonary fibrosis, restenosis, asthma, psoriasis, inflammatory bowel disease, multiple sclerosis and transplant rejection, in a mammal in need thereof, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof.
It is also encompassed within the scope of the present invention a pharmaceutical composition which comprises a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the treatment or prevention of disorders associated with the activation of the transcription factor NF-xcexaB and/or the expression of genes which are dependent on this transcription factor, and more preferably for the treatment or prevention of inflammation; asthma; adult respiratory distress syndrome (ARDS); immunoinflammatory and autoimmune diseases such as rheumatoid arthritis and other arthritic conditions, multiple sclerosis, psoriasis, inflammatory bowel disease, lupus and glomerulonephritis; arthrosis; septic shock; atherosclerosis; cancer; osteoporosis; preterm labour; transplant rejection; neurodegenerative diseases such as dementia, including Alzheimer""s disease, Parkinson""s disease and amyotrophic lateral sclerosis; and viral infections.
The pharmaceutically acceptable salts of a compound of formula I include any of the salts commonly used in pharmaceutical chemistry, such as for example the salts with inorganic cations such as sodium, potassium, calcium, magnesium, lithium, aluminium, zinc, etc as well as the salts formed with ammonia and other pharmaceutically acceptable amines.
Throughout the present description, the term prodrug of a compound of formula I means any precursor compound of a compound of formula I that is capable of being metabolized and release in vivo a compound of formula 1, that is triflusal or HTB.
By NF-xcexaB it is to be understood any member of the family of proteins known by this name.
By gene which is dependent on and/or regulated by, at least partially, the transcription factor NF-xcexaB it is to be understood any gene having in its promoter region one or more NF-xcexaB binding sites. The list of genes regulated by NF-xcexaB mentioned above under the heading xe2x80x9cDescription of the prior artxe2x80x9d is cited only as an example and it is not to be understood as limiting the scope of the invention in any way.
By disorder associated with the activation of the transcription factor NF-xcexaB and/or the expression of genes which are dependent on this transcription factor it is to be understood any disease or pathological state where the activation of NF-xcexaB and/or the proteins whose expression (i.e. the expression of the gene that encodes them) is regulated by this transcription factor are involved, at least partially. The lists of these diseases mentioned above are cited only as examples and thus are not to be understood as limiting the scope of the present invention in any case.
The term neurodegenerative diseases includes, among others, dementias, such as Alzheimer""s disease; diseases involving movement dysfunction, such as Parkinson""s disease; progressive ataxias; and amyotrophies of neuronal origin, such as amyotrophic lateral sclerosis.
By the term dementia it is to be understood any pathology characterized by an impairment of the cognitive functions, such as for example Alzheimer""s disease, post-traumatic dementia or dementia following infection as well as mixed situations.
The term inflammatory bowel disease includes both ulcerative colitis and Crohn""s disease as well as any other type of variant of inflammatory bowel disease.
The term transplant rejection refers both to tissue transplant rejection, such as for example graft-versus-host disease, as well as organ transplant rejection.
Processes for preparing triflusal or HTB are disclosed in the above-mentioned US patent (U.S. Pat. No. 4,096,252).
As mentioned above, the compounds of formula I inhibit the activation of the transcription factor NF-xcexaB and therefore can be used to inhibit said activation in mammals, preferably in human beings. The dose of a compound of formula I necessary to modulate the activation of the transcription factor NF-xcexaB, or any other use herein described, will depend upon the disorder to be treated, the severity of the symptoms, the age and body weight of the patient as well as the chosen route of administration. Any person skilled in the art will be able to readily determine the appropriate doses depending on these factors without having to incur in undue experimentation. In human therapy, doses will generally be in the range between about 30 mg and about 3000 mg daily of a compound of formula I, which can be administered in one or several dosage units. Depending on the particular disease to be treated and the patient""s situation, however, doses outside this range might be needed, which, as mentioned above, may be readily determined by those skilled in the art without requiring undue experimentation.
The compounds of formula I can be administered in the form of any pharmaceutical formulation, the nature of which will depend, as it is well known, upon the route of administration and the nature of the disease to be treated. These pharmaceutical compositions can be prepared by conventional methods, using compatible, pharmaceutically-acceptable excipients or vehicles. Examples of such compositions include capsules, tablets, syrups, powders and granulates for the preparation of extemporaneous solutions, injectable preparations, etc. A preferred route of administration for the compounds of formula I is by the oral route. For example, they can be administered as hard gelatine capsules containing for example 50, 100, 200, 300, 400 or 500 mg of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof.